Interleukin-15 response signature predicts RhCMV/SIV vaccine efficacy

Simian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with strain 68–1 Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in ~55% of vaccinated RMs with no protection in the remaining 45%. Although previous work indicates that unconventionally restricted, SIV-specific, effector-memory (EM)-biased CD8+ T cell responses are necessary for efficacy, the magnitude of these responses does not predict efficacy, and the basis of protection vs. non-protection in 68–1 RhCMV/SIV vector-vaccinated RMs has not been elucidated. Here, we report that 68–1 RhCMV/SIV vector administration strikingly alters the whole blood transcriptome of vaccinated RMs, with the sustained induction of specific immune-related pathways, including immune cell, toll-like receptor (TLR), inflammasome/cell death, and interleukin-15 (IL-15) signaling, significantly correlating with subsequent vaccine efficacy. Treatment of a separate RM cohort with IL-15 confirmed the central involvement of this cytokine in the protection signature, linking the major innate and adaptive immune gene expression networks that correlate with RhCMV/SIV vaccine efficacy. This change-from-baseline IL-15 response signature was also demonstrated to significantly correlate with vaccine efficacy in an independent validation cohort of vaccinated and challenged RMs. The differential IL-15 gene set response to vaccination strongly correlated with the pre-vaccination activity of this pathway, with reduced baseline expression of IL-15 response genes significantly correlating with higher vaccine-induced induction of IL-15 signaling and subsequent vaccine protection, suggesting that a robust de novo vaccine-induced IL-15 signaling response is needed to program vaccine efficacy. Thus, the RhCMV/SIV vaccine imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8+ T cell function, that support the ability of vaccine-elicited unconventionally restricted CD8+ T cells to mediate protection against SIV challenge.

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Probiotic supplementation in marathonists and its impact on lymphocyte population and function after a marathon: a randomized placebo-controlled double-blind study

Scientific Reports ◽

10.1038/s41598-020-75464-0 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Helena Batatinha ◽

Edgar Tavares-Silva ◽

Geovana S. F. Leite ◽

Ayane S. Resende ◽

José A. T. Albuquerque ◽

...

Keyword(s):

T Cell ◽

Acute Exercise ◽

Cell Function ◽

Immune Cell ◽

Cd8 T Cell ◽

Effector Memory ◽

Double Blind Study ◽

Lymphocyte Population ◽

Probiotic Supplementation ◽

Double Blind

Abstract Probiotic supplementation arises as playing an immune-stimulatory role. High-intensity and -volume exercise can inhibit immune cell function, which threatens athletic performance and recovery. We hypothesized that 30 days of probiotic supplementation could stabilize the immune system of athletes preventing immune suppression after a marathon race. Twenty-seven male marathonists were double-blinded randomly into probiotic (Bifidobacterium-animalis-subsp.-Lactis (10 × 109) and Lactobacillus-Acidophilus (10 × 109) + 5 g of maltodextrin) and placebo (5 g of maltodextrin) group. They received 30 sachets and supplemented 1 portion/day during 30 days before the race. Blood were collected 30 days before (rest), 1 day before (pre), 1 h after (post) and 5 days after the race (recovery). Both chronic and acute exercise modulated a different T lymphocyte population (CD3+CD4−CD8− T-cells), increasing pre-race, decreasing post and returning to rest values at the recovery. The total number of CD8 T cell and the memory subsets statistically decreased only in the placebo group post-race. Pro-inflammatory cytokine production by stimulated lymphocytes decreased in the probiotic group after the supplementation period. 30 days of probiotic supplementation maintained CD8 T cell and effector memory cell population and played an immunomodulatory role in stimulated lymphocytes. Both, training and marathon modulated a non-classical lymphocyte population regardless of probiotic supplementation.

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Tumors induce de novo steroid biosynthesis in T cells to evade immunity

10.1101/471359 ◽

2018 ◽

Cited By ~ 1

Author(s):

Bidesh Mahata ◽

Jhuma Pramanik ◽

Louise van der Weyden ◽

Krzysztof Polanski ◽

Gozde Kar ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

Tumor Immunity ◽

Cell Function ◽

Immune Cell ◽

De Novo ◽

Steroid Biosynthesis ◽

Genetic Ablation ◽

Tumor Immunosuppression

ABSTRACTTumors subvert immune cell function to evade immune responses, yet the complex mechanisms driving immune evasion remain poorly understood. Here we show that tumors induce de novo steroidogenesis in T lymphocytes to evade anti-tumor immunity. Using a novel transgenic steroidogenesis-reporter mouse line we identify and characterize de novo steroidogenic immune cells. Genetic ablation of T cell steroidogenesis restricts primary tumor growth and metastatic dissemination in mouse models. Steroidogenic T cells dysregulate anti-tumor immunity, and inhibition of the steroidogenesis pathway was sufficient to restore anti-tumor immunity. This study demonstrates T cell de novo steroidogenesis as a mechanism of anti-tumor immunosuppression and a potential druggable target.

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Sustained IL-15 response signature predicts RhCMV/SIV vaccine efficacy

10.1101/2021.01.11.426199 ◽

2021 ◽

Author(s):

Fredrik Barrenäs ◽

Scott G. Hansen ◽

Lynn Law ◽

Connor Driscoll ◽

Richard R. Green ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

Cell Death ◽

T Cell ◽

Cell Function ◽

Effector Memory ◽

Highly Pathogenic ◽

Cell Responses ◽

Adaptive Immune ◽

Immune Pathways

AbstractSimian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in ~55% of vaccinated RMs with no protection in the remaining 45%. Although previous work suggests that unconventionally restricted, SIV-specific, effector-memory (EM)-biased CD8+ T cell responses are necessary for efficacy, the magnitude of these responses does not predict efficacy, and the basis of protection vs. non-protection in RhCMV/SIV vector-vaccinated RMs has not been elucidated. Here, we report that RhCMV/SIV vector administration strikingly alters the whole blood transcriptome of vaccinated RMs, with the sustained induction of specific immune-related pathways, including non-canonical T cell receptor (TCR), toll-lie receptor (TLR), inflammasome/cell death, and interleukin-15 (IL-15) signaling, significantly predicting protection. The IL-15 gene expression signature was further evaluated in an independent RM IL-15 treatment cohort, revealing that in whole blood the response to IL-15 is inclusive of innate and adaptive immune gene expression networks that link with RhCMV/SIV vaccine efficacy. We also show that this IL-15 response signature similarly tracks with vaccine protection in an independent RhCMV/SIV vaccination/SIV challenge RM validation cohort. Thus, the RhCMV/SIV vaccine imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8+ T cell function, that enable vaccine-elicited CD8+ T cells to mediate protection against highly pathogenic SIV challenge.Author SummarySIV insert-expressing vaccine vectors based on strain 68-1 RhCMV elicit robust, highly effector-memory-biased T cell responses that are associated with an unprecedented level of SIV control after challenge (replication arrest leading to clearance) in slightly over half of vaccinated monkeys. Since efficacy is not predicted by standard measures of immunogenicity, we used functional genomics analysis of RhCMV/SIV vaccinated monkeys with known challenge outcomes to identify immune correlates of protection. We found that arrest of viral replication after challenge significantly correlates with a vaccine-induced response to IL-15 that includes modulation of T cell, inflammation, TLR signaling, and cell death programming. These data suggest that RhCMV/SIV efficacy is not based on chance, but rather, results from a coordinated and sustained vaccine-mediated induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8+ effector-memory T cell function, that enable vaccine-elicited CD8+ T cells to mediate efficacy.

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Low CD4+ T-cell counts in HIV patients receiving effective antiretroviral therapy are associated with CD4+ T-cell activation and senescence but not with lower effector memory T-cell function

Clinical Immunology ◽

10.1016/j.clim.2006.04.570 ◽

2006 ◽

Vol 120 (2) ◽

pp. 163-170 ◽

Cited By ~ 42

Author(s):

Sonia Fernandez ◽

Patricia Price ◽

Elizabeth J. McKinnon ◽

Richard C. Nolan ◽

Martyn A. French

Keyword(s):

T Cell ◽

Antiretroviral Therapy ◽

T Cell Activation ◽

Cell Activation ◽

Cell Function ◽

Cd4 T Cell ◽

Effector Memory ◽

Hiv Patients ◽

Memory T Cell ◽

Cell Counts

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Functionally specialized human CD4+ T-cell subsets express physicochemically distinct TCRs

eLife ◽

10.7554/elife.57063 ◽

2020 ◽

Vol 9 ◽

Author(s):

Sofya A Kasatskaya ◽

Kristin Ladell ◽

Evgeniy S Egorov ◽

Kelly L Miners ◽

Alexey N Davydov ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptors ◽

Adaptive Immune System ◽

T Cell Subsets ◽

Effector Memory ◽

Intrinsic Properties ◽

Antigen Specificity ◽

Adaptive Immune ◽

Transition Pathways

The organizational integrity of the adaptive immune system is determined by functionally discrete subsets of CD4+ T cells, but it has remained unclear to what extent lineage choice is influenced by clonotypically expressed T-cell receptors (TCRs). To address this issue, we used a high-throughput approach to profile the αβ TCR repertoires of human naive and effector/memory CD4+ T-cell subsets, irrespective of antigen specificity. Highly conserved physicochemical and recombinatorial features were encoded on a subset-specific basis in the effector/memory compartment. Clonal tracking further identified forbidden and permitted transition pathways, mapping effector/memory subsets related by interconversion or ontogeny. Public sequences were largely confined to particular effector/memory subsets, including regulatory T cells (Tregs), which also displayed hardwired repertoire features in the naive compartment. Accordingly, these cumulative repertoire portraits establish a link between clonotype fate decisions in the complex world of CD4+ T cells and the intrinsic properties of somatically rearranged TCRs.

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BCG vaccination induces enhanced frequencies of memory T cells and altered plasma levels of common γc cytokines in elderly individuals

PLoS ONE ◽

10.1371/journal.pone.0258743 ◽

2021 ◽

Vol 16 (11) ◽

pp. e0258743

Author(s):

Nathella Pavan Kumar ◽

Chandrasekaran Padmapriyadarsini ◽

Anuradha Rajamanickam ◽

Perumal Kannabiran Bhavani ◽

Arul Nancy ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

T Cell ◽

Cd8 T Cells ◽

Plasma Levels ◽

T Cell Subsets ◽

Effector Memory ◽

Elderly Individuals ◽

Bcg Vaccination ◽

Adaptive Immune

BCG vaccination is known to induce innate immune memory, which confers protection against heterologous infections. However, the effect of BCG vaccination on the conventional adaptive immune cells subsets is not well characterized. We investigated the impact of BCG vaccination on the frequencies of T cell subsets and common gamma c (γc) cytokines in a group of healthy elderly individuals (age 60–80 years) at one month post vaccination as part of our clinical study to examine the effect of BCG on COVID-19. Our results demonstrate that BCG vaccination induced enhanced frequencies of central (p<0.0001) and effector memory (p<0.0001) CD4+ T cells and diminished frequencies of naïve (p<0.0001), transitional memory (p<0.0001), stem cell memory (p = 0.0001) CD4+ T cells and regulatory T cells. In addition, BCG vaccination induced enhanced frequencies of central (p = 0.0008), effector (p<0.0001) and terminal effector memory (p<0.0001) CD8+ T cells and diminished frequencies of naïve (p<0.0001), transitional memory (p<0.0001) and stem cell memory (p = 0.0034) CD8+T cells. BCG vaccination also induced enhanced plasma levels of IL-7 (p<0.0001) and IL-15 (p = 0.0020) but diminished levels of IL-2 (p = 0.0033) and IL-21 (p = 0.0020). Thus, BCG vaccination was associated with enhanced memory T cell subsets as well as memory enhancing γc cytokines in elderly individuals, suggesting its ability to induce non-specific adaptive immune responses.

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Prolonged activation of nasal immune cell populations and development of tissue-resident SARS-CoV-2 specific CD8 T cell responses following COVID-19

10.1101/2021.04.19.21255727 ◽

2021 ◽

Author(s):

Anna H.E. Roukens ◽

Marion König ◽

Tim Dalebout ◽

Tamar Tak ◽

Shohreh Azimi ◽

...

Keyword(s):

T Cells ◽

Immune System ◽

T Cell ◽

Nasal Mucosa ◽

Immune Cell ◽

Inflammatory Responses ◽

Upper Airway ◽

Effector Memory ◽

Long Term Effects ◽

Activated T Cells

AbstractThe immune system plays a major role in Coronavirus Disease 2019 (COVID-19) pathogenesis, viral clearance and protection against re-infection. Immune cell dynamics during COVID-19 have been extensively documented in peripheral blood, but remain elusive in the respiratory tract. We performed minimally-invasive nasal curettage and mass cytometry to characterize nasal immune cells of COVID-19 patients during and 5-6 weeks after hospitalization. Contrary to observations in blood, no general T cell depletion at the nasal mucosa could be detected. Instead, we observed increased numbers of nasal granulocytes, monocytes, CD11c+ NK cells and exhausted CD4+ T effector memory cells during acute COVID-19 compared to age-matched healthy controls. These pro-inflammatory responses were found associated with viral load, while neutrophils also negatively correlated with oxygen saturation levels. Cell numbers mostly normalized following convalescence, except for persisting CD127+ granulocytes and activated T cells, including CD38+ CD8+ tissue-resident memory T cells. Moreover, we identified SARS-CoV-2 specific CD8+ T cells in the nasal mucosa in convalescent patients. Thus, COVID-19 has both transient and long-term effects on the immune system in the upper airway.

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Clinically-Relevant Rapamycin Treatment Regimens Enhance CD8+Effector Memory T Cell Function In The Skin and Allow their Infiltration into Cutaneous Squamous Cell Carcinoma

OncoImmunology ◽

10.1080/2162402x.2018.1479627 ◽

2018 ◽

Vol 7 (9) ◽

pp. e1479627 ◽

Cited By ~ 5

Author(s):

Ji-Won Jung ◽

Margaret Veitch ◽

Jennifer A. Bridge ◽

Nana H. Overgaard ◽

Jazmina L. Cruz ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

T Cell ◽

Cell Carcinoma ◽

Squamous Cell ◽

Cell Function ◽

Cutaneous Squamous Cell Carcinoma ◽

Effector Memory ◽

Rapamycin Treatment ◽

Memory T Cell ◽

Treatment Regimens

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Manipulation of Glucose Availability to Boost Cancer Immunotherapies

Cancers ◽

10.3390/cancers12102940 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2940

Author(s):

Federica Marchesi ◽

Debora Vignali ◽

Beatrice Manini ◽

Alessandra Rigamonti ◽

Paolo Monti

Keyword(s):

T Cell ◽

Metabolic Regulation ◽

Cell Function ◽

Immune Cell ◽

Deep Level ◽

T Cell Responses ◽

Cell Responses ◽

T Cell Function ◽

Cancer Tissues ◽

Cancer Immunotherapies

The orchestration of T cell responses is intimately linked to the execution of metabolic processes, both in homeostasis and disease. In cancer tissues, metabolic alterations that characterize malignant transformation profoundly affect the composition of the immune microenvironment and the accomplishment of an effective anti-tumor response. The growing understanding of the metabolic regulation of immune cell function has shed light on the possibility to manipulate metabolic pathways as a strategy to improve T cell function in cancer. Among others, glucose metabolism through the glycolytic pathway is central in shaping T cell responses and emerges as an ideal target to improve cancer immunotherapy. However, metabolic manipulation requires a deep level of control over side-effects and development of biomarkers of response. Here, we summarize the metabolic control of T cell function and focus on the implications of metabolic manipulation for the design of immunotherapeutic strategies. Integrating our understanding of T cell function and metabolism will hopefully foster the forthcoming development of more effective immunotherapeutic strategies.

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